This invention describes an improved, more economical process for synthesis of encainide (I) ##STR1## which is suitable for large scale manufacture. Encainide, chemically, 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, is a member of a series of antiarrhythmic 2-phenethylpiperidines bearing amide substituents in the ortho-position of the phenyl ring. Encainide hydrochloride is also referred to in the literature as MJ 9067-1 (USAN and the USP Dictionary of Drug Names, 1980, p. 122, United States Pharmacopeal Convention, Inc., 12601 Twinbrook Parkway, Rockville, Md. 20852, Library of Congress Catalog Card No. 72-88571). Currently, encainide is undergoing clinical evaluation as an effective antiarrhythmic agent.
Previous synthesis of encainide and closely related compounds is described in the following references.
Dykstra, S. J., et al., J. Med. Chem., 16, 1015-1020 (1973). PA1 S. J. Dykstra and J. L. Minielli, U.S. Pat. No. 3,931,195 patented Jan. 6, 1967; U.S. Pat. No. 4,000,143 patented Dec. 28, 1978; U.S. Pat. No. 4,064,254 patented Dec. 20, 1977. PA1 Byrne, J. E., et al., J. Pharmacology and Experimental Therapeutics, 200, 147-154 (1977). PA1 1. H. Stephan and G. Wadge, J. Chem. Soc., 4420 (1956). This reference describes methyl N-p-anisoyl anthranilate, an intermediate produced in the instant process. PA1 2a. J. F. Wolfe, D. E. Portlock and D. J. Feuerbach, Journal of Organic Chemistry, 39, 2006-2010 (1974). PA1 2b. R. Levine and S. Reynolds, J. Organic Chemistry, 25, 530-537 (1960). PA1 2c. N. Goldberg and R. Levine, Journal Americal Chemical Society, 74, 5217-5219 (1952). PA1 2d. N. Goldberg, L. Barkley, and R. Levine Journal American Chemical Society, 73, 4301-4303 (1951).
The process, as disclosed in the above cited references, which has been used for preparation of encainide is shown in Scheme 1. ##STR2##
The first step of the process outlined in Scheme 1 involves starting with ortho-nitrobenzaldehyde (1), a relatively expensive material, and one objective of the instant invention was to devise a process starting with a more readily available, less expensive, starting material. Work up of the reaction mixture of step 3 of Scheme 1 gives a red oil which is dissolved in acetonitrile and treated with dimethylsulfate (3b), a toxic alkylating agent, yielding 2-[2-[2-(4-methoxybenazmido)phenyl]ethyl]-1-methylpyridinium methylsulfate (5). Step 4 is the hydrogenation of an alcoholic solution of (5) using a platinum catalyst.
The prior art method represented by Scheme 1 is thus a multiple step process using expensive and hazardous raw materials. In contrast, the process of the instant invention uses a less expensive commercially available starting material; requires less labor; avoids toxic alkylating agents; and, in total, provides high quality encainide at lower cost.
The following references relate to component steps of the instant process described herein.
These references describe the acylation of metalated methyl heteroaromatics with non-enolizable esters; addressing the scope, mechanism, and application of the reaction. The acylation of metalated 2-picoline in the instant process is one specific application of this reaction type.